Part of placebo effect ascribed to cannabinoids

A drug that blocks signaling through the cannabinoid receptor can block some …

In clinical trials, new drugs are often compared to older treatments, but sometimes they're also compared to placebos—inert treatments that ought to have no effect. Except that's not what happens. The placebo effect can actually be pretty strong, and even more strangely, placebos can work even when the patient knows they're being given one.

Most of what we know about placebos results from studies on how we process pain, since it's more ethical to give someone a placebo instead of a painkiller than it would be to replace an anti-cancer drug or insulin. Some of the analgesic (painkilling) effect of placebo treatment is due to endogenous opioids, ones made by the body. Now, evidence has emerged that suggests an additional effect results from the cannabinoid pathway, according to a publication in Nature Medicine.

Placebo-activated opioid analgesia doesn't work all the time. Experimentally, researchers can induce it by preconditioning a research subject with an actual opioid analgesic. Or, to explain that in plain English, you give the subject a painful stimulus then give them an opioid to treat it. You do this several times then, instead of giving them a real drug, you give them a placebo, which will block the pain. What's more, you can actually inhibit the action of the placebo by giving the subject an opioid antagonist like naloxone, which blocks the effect of opioids. Still with me? Good.

Here's where things get more complicated. You can also use a nonsteroidal anti-inflammatory (NSAID), like ibuprofen, to create a placebo analgesic effect. But this time, it can't be blocked with naloxone. So there's more than one biochemical pathway responsible for the analgesic effects of sugar pills. The new paper involves an attempt to look for alternate pathways.

The Nature Medicine study involved several test groups, and measured their pain response to a tourniquet on five non-consecutive days. The first group receive no treatment at all during the study, and they showed no variation in pain threshold across its duration. A second group was given morphine on days 2 and 3, and a placebo on day 4, which had the same analgesic effect as morphine. The normal placebo effect worked.

A third group were given, without their knowledge (beyond general informed consent) a drug called rimbonant (marketed as Accomplia and also know as SR141716A). Rimbonant largely works by blocking a receptor called CB1. CB1 is activated in the body by a molecule called anandamide, and it's also the same receptor that cannabinoids activate. Rimbonant didn't have any effect on pain tolerance in this group, which had very similar responses to the subjects who received no drugs at all in the study. From this we can infer that blocking cannabinoid signaling through CB1 has no effect on the type of pain being measured.

Another group got the morphine treatment described above, but also got rimbonant with the placebo. Again, in this group, rimbonant had no effect, meaning that the opioid placebo effect isn't working through the body's cannabinoid pathway.

Finally, there were two more groups that were given ketorolac—an NSAID—instead of morphine on days 2 and 3. One of these groups was given a placebo on day 4, which worked just as well as ketorolac.

The other group got a placebo plus rimbonant. Normally, the placebo would block the pain but, in this case the rimbonant+placebo had no effect. This indicates that rimbonant blocked the placebo effect. This suggests that cannabinoids are playing an important role in nonopioid preconditioned placebo effects.

I should mention that this was only a fairly small study, and more work needs to be done in the area to fully flesh out this idea. Rimbonant can also have effects that are not all mediated through CB1 receptors, as I found out during the course of my Ph.D. But it is a neat little study, and one that expands our understanding of the pharmacology of placebos, to the degree such a thing is possible.

Crowd: We need a cure! We need a cure!Dr. Hibbert: Why, the only cure is bed rest. Anything I give you would only be a placebo.Blonde Woman: Where do we get these placebos?Man: Maybe there's some in this truck![the panicky crowd push over a truck, boxes labeled "danger killer bees" break open, the bees go everywhere and everyone panics, one man puts a bee in his mouth]Man: I'm cured! I mean, ouch!

I wonder if the same reverse effect could be measured: the scientists believe that a certain effect will not work, so it doesn't. In the case of marijuana, a cheap weed that can survive in drougt, can grow faster and hardier than a great number of other plants, can actually do a lot of good for people, sick or healthy. They don't want that kind of thing to work. They want expensive patented medicines to work. Folks here moan about software patents but say so little when it comes to the outrageous monopoly that the doctors have over our own bodies. It's ludicrous. I am willing to bet this study will soon be touted by the anti-freedom-pro-Christian-creationist-facist groups that abound throughout the deluded 'free world'.

I wonder if the same reverse effect could be measured: the scientists believe that a certain effect will not work, so it doesn't. In the case of marijuana, a cheap weed that can survive in drougt, can grow faster and hardier than a great number of other plants, can actually do a lot of good for people, sick or healthy. They don't want that kind of thing to work. They want expensive patented medicines to work. Folks here moan about software patents but say so little when it comes to the outrageous monopoly that the doctors have over our own bodies. It's ludicrous. I am willing to bet this study will soon be touted by the anti-freedom-pro-Christian-creationist-facist groups that abound throughout the deluded 'free world'.

I think you are missing the point here. The placebo effect cannot be patented. These researchers are trying to figure out exactly how it works because this effect can be exploited to reduce pain without any harmful side effects. Additionally, many of patented drugs actually don't fare too well against a placebo, so by better understanding the phenomena, we can only accept new drugs that truly perform.

So basically the body gets used to certain chemical triggers during use of painkillers in everyday life, so that when it gets stimuli associated with those triggers at some later time there is a "Pavlovian" response?

edit: if this is right, one could potentially train people to trigger this at will...

I wonder if the same reverse effect could be measured: the scientists believe that a certain effect will not work, so it doesn't. In the case of marijuana, a cheap weed that can survive in drougt, can grow faster and hardier than a great number of other plants, can actually do a lot of good for people, sick or healthy. They don't want that kind of thing to work. They want expensive patented medicines to work. Folks here moan about software patents but say so little when it comes to the outrageous monopoly that the doctors have over our own bodies. It's ludicrous. I am willing to bet this study will soon be touted by the anti-freedom-pro-Christian-creationist-facist groups that abound throughout the deluded 'free world'.

I think you are missing the point here. The placebo effect cannot be patented. These researchers are trying to figure out exactly how it works because this effect can be exploited to reduce pain without any harmful side effects. Additionally, many of patented drugs actually don't fare too well against a placebo, so by better understanding the phenomena, we can only accept new drugs that truly perform.

"Part of placebo effect ascribed to cannabinoids"

That's the glaring headline that I did not miss. Don't you think it's curious why they chose that particular drug to do the study on? They didn't choose something like Tylenol, did they? This 'study' seems to have a political motive.

That's the glaring headline that I did not miss. Don't you think it's curious why they chose that particular drug to do the study on? They didn't choose something like Tylenol, did they? This 'study' seems to have a political motive.

You do realize that your body produces cannabinoids, and that there are neural receptors in the brain for them, right? They didn't give anyone marijuana or THC pills. Seriously, read more fully and try to understand it before posting.

Tylenol = active drug blocking an enzyme in the inflammation/pain pathway.Placebo = non-active substance that can induce active effects if the person thinks it is a drug.

The question they were addressing is how placebos work. Which, according to this study, is in part by activating cannabinoid receptors.

Here's where things get more complicated. You can also use a nonsteroidal anti-inflammatory (NSAID), like ibuprofen, to create a placebo analgesic effect.

Is this saying that NSAIDs don't have a real analgesic effect; that they just act as a placebo as far as pain goes?

Quote:

Another group got the morphine treatment described above, but also got rimbonant with the placebo. Again, in this group, rimbonant had no effect, meaning that the opioid placebo effect isn't working through the body's cannabinoid pathway.

Does that mean that the placebo affect occurred with this group, just like the first group, or that the rimbonant+placebo had no effect?

So.... Essentially since placebo is meant to trick a test subject into thinking something is happening when it's not, they've effectively made a drug to partially block the imagination?

(Couldn't they have just sat their test subjects in front of a television and accomplished the same thing?)

Edit: Now that I think about it, how could this potentially be applied to situations of "opposite case scenarios", i.e. Hypochondriacs?

The placebo effect, while perhaps partially mediated by something like "imagination", isn't entirely in your mental state. Consider an experiment that was done some time ago: a group of researchers were testing an immunosuppressant drug in rats. (Or perhaps the immunosuppressant was secondary to another research objective. I don't recall.) The drug was administered by mixing it with sugar water.

...after the research ended, the researchers continued to give the rats ordinary sugar water. Shortly thereafter, all of the rats died from massive systemic infections. Investigation revealed their immune systems were almost completely suppressed.

So, rats that do not quite have an "imagination" in the sense you describe have still been killed by something which pretty much falls under the "placebo effect" heading.

Also, someone referenced active placebos. In case someone doesn't know what they are: active placebos are pills that you give to someone that causes physical side effects, but is known to have no bearing on treating the condition you are testing the drug on. So subjects get a pill that has effects, and it seems to work better than the normal placebo effect.

Here's where things get more complicated. You can also use a nonsteroidal anti-inflammatory (NSAID), like ibuprofen, to create a placebo analgesic effect.

Is this saying that NSAIDs don't have a real analgesic effect; that they just act as a placebo as far as pain goes?

It's a bit clearer if you look at the paper itself. NSAIDs act by inhibiting Cox-2. However, they also have an opiod-dependent effect which is separate from Cox-2 inhibition, so they have both a real effect and a placebo effect.

pavon wrote:

Quote:

Another group got the morphine treatment described above, but also got rimbonant with the placebo. Again, in this group, rimbonant had no effect, meaning that the opioid placebo effect isn't working through the body's cannabinoid pathway.

Does that mean that the placebo affect occurred with this group, just like the first group, or that the rimbonant+placebo had no effect?

I wonder if the same reverse effect could be measured: the scientists believe that a certain effect will not work, so it doesn't. In the case of marijuana, a cheap weed that can survive in drougt, can grow faster and hardier than a great number of other plants, can actually do a lot of good for people, sick or healthy. They don't want that kind of thing to work. They want expensive patented medicines to work. Folks here moan about software patents but say so little when it comes to the outrageous monopoly that the doctors have over our own bodies. It's ludicrous. I am willing to bet this study will soon be touted by the anti-freedom-pro-Christian-creationist-facist groups that abound throughout the deluded 'free world'.

I think you are missing the point here. The placebo effect cannot be patented. These researchers are trying to figure out exactly how it works because this effect can be exploited to reduce pain without any harmful side effects. Additionally, many of patented drugs actually don't fare too well against a placebo, so by better understanding the phenomena, we can only accept new drugs that truly perform.

"Part of placebo effect ascribed to cannabinoids"

That's the glaring headline that I did not miss. Don't you think it's curious why they chose that particular drug to do the study on? They didn't choose something like Tylenol, did they? This 'study' seems to have a political motive.

Rimbonant is actually a cannabinoid antagonist, not agonist. Thus, this is the first point you missed. In fact, this article would suggest that marijuana would potentiate one pathway involved in the placebo effect, thus having a clinical benefit. In order to show that the NSAID-mediated pathway involved the cannabinoid receptor, they had to block the pathway, not stimulate it as marijuana would do. Furthermore, this drug is not actually used in clinical practice. They are not trying to market this drug to doctors because, as you might realize by now, it can only make people feel worse.

pavon wrote:

Does that mean that the placebo affect occurred with this group, just like the first group, or that the rimbonant+placebo had no effect?

This means that it had no effect. The opioid pathway for placebo effect cannot be attenuated by blocking the cannabinoid pathway

Here's where things get more complicated. You can also use a nonsteroidal anti-inflammatory (NSAID), like ibuprofen, to create a placebo analgesic effect.

Is this saying that NSAIDs don't have a real analgesic effect; that they just act as a placebo as far as pain goes?

No. It's a *preconditioned* placebo response. Day 1, you give the patient a painful stimulus. Day 2, you do the same, then give them an NSAID or opiod, and that makes the pain go away. Day 3, do the same thing. Day 4, give them a placebo instead of a real drug, and despite it not being an active drug it works just as well as the drug you gave them on day 2 or day 3.

That's the glaring headline that I did not miss. Don't you think it's curious why they chose that particular drug to do the study on? They didn't choose something like Tylenol, did they? This 'study' seems to have a political motive.

You do realize that your body produces cannabinoids, and that there are neural receptors in the brain for them, right? They didn't give anyone marijuana or THC pills. Seriously, read more fully and try to understand it before posting.

Tylenol = active drug blocking an enzyme in the inflammation/pain pathway.Placebo = non-active substance that can induce active effects if the person thinks it is a drug.

The question they were addressing is how placebos work. Which, according to this study, is in part by activating cannabinoid receptors.

I took a look at the brief that was linked to from this article. The title says 'Nonopioid placebo analgesia is mediated by CB1 cannabinoid receptors,' which is a whole lot different than what the title of this Ars article says. You are right in so far as that the study itself had nothing to do with cannibinoids and everything to do with cannibinoid receptors. However, the title of this article implies that cannibinoids had something to do with this study, which from what little I could glean from the article and the introduction. A better title might have been, "Part of placebo effect ascribed to cannabinoid receptors," since it is the receptor that is the target of the study, and not cannabinoids. There is a big difference.

I did a little digging around. Feel free to correct me if the need arises, but the 'cannibinoids' which the body manufactures seems to be referred to as endocannabinoids rather than cannibinoids. So, maybe the problem here is with the author's/editor's choice for a title.

I wonder if the same reverse effect could be measured: the scientists believe that a certain effect will not work, so it doesn't. In the case of marijuana, a cheap weed that can survive in drougt, can grow faster and hardier than a great number of other plants, can actually do a lot of good for people, sick or healthy. They don't want that kind of thing to work. They want expensive patented medicines to work. Folks here moan about software patents but say so little when it comes to the outrageous monopoly that the doctors have over our own bodies. It's ludicrous. I am willing to bet this study will soon be touted by the anti-freedom-pro-Christian-creationist-facist groups that abound throughout the deluded 'free world'.

...

wat?

wordsworm wrote:

"Part of placebo effect ascribed to cannabinoids"

That's the glaring headline that I did not miss. Don't you think it's curious why they chose that particular drug to do the study on? They didn't choose something like Tylenol, did they? This 'study' seems to have a political motive.

wordsworm wrote:

I took a look at the brief that was linked to from this article. ...You are right in so far as that the study itself had nothing to do with cannibinoids and everything to do with cannibinoid receptors. However, the title of this article implies that cannibinoids had something to do with this study, which from what little I could glean from the article and the introduction. A better title might have been, "Part of placebo effect ascribed to cannabinoid receptors," since it is the receptor that is the target of the study, and not cannabinoids. There is a big difference.

ಠ_ಠ

Quote:

I did a little digging around. Feel free to correct me if the need arises, but the 'cannibinoids' which the body manufactures seems to be referred to as endocannabinoids rather than cannibinoids. So, maybe the problem here is with the author's/editor's choice for a title.

I think the problem here is that you see "cannabinoids" and latch onto the totally unrelated legal issues of marijuana like Smokey on a roach. Cannabinoid receptors respond to cannabinoids specificially. It doesn't matter if they come from phytocannabinoids, endocannabinoids, or synthetic cannabinoids. This study indicates that cannabiniods (most likely the kind your body makes for itself, like anandamide) are somehow involved in the placebo effect when pain relief operating through the cannabinoid pathways are expected but absent, or else blocking the receptors for them with rimbonant probably wouldn't work. If the body is expecting a pain reliever to go through the opioid pathway (like the group conditioned with morphine), using rimbonant does nothing to stop the placebo effect. So basically it seems there are several ways to get a placebo, and the cannabinoids your body makes may be involved unless you tell it otherwise by giving it an opioid to use.

So.... Essentially since placebo is meant to trick a test subject into thinking something is happening when it's not, they've effectively made a drug to partially block the imagination?

(Couldn't they have just sat their test subjects in front of a television and accomplished the same thing?)

Edit: Now that I think about it, how could this potentially be applied to situations of "opposite case scenarios", i.e. Hypochondriacs?

Well, it's been shown in several studies that the "placebo effect" is an actual chemical reaction, though still not fully understood. They gave patients a placebo morphine...just telling them they were getting morphine and the ones that responded to it were then secretly given a drug that blocks morphine, in other words, they weren't told at all they were getting the morphine blocker, and they started receiving pain again. The fake morphine was being blocked as if it were real.

That's the glaring headline that I did not miss. Don't you think it's curious why they chose that particular drug to do the study on? They didn't choose something like Tylenol, did they? This 'study' seems to have a political motive.

You do realize that your body produces cannabinoids, and that there are neural receptors in the brain for them, right? They didn't give anyone marijuana or THC pills. Seriously, read more fully and try to understand it before posting.

Tylenol = active drug blocking an enzyme in the inflammation/pain pathway.Placebo = non-active substance that can induce active effects if the person thinks it is a drug.

The question they were addressing is how placebos work. Which, according to this study, is in part by activating cannabinoid receptors.

I took a look at the brief that was linked to from this article. The title says 'Nonopioid placebo analgesia is mediated by CB1 cannabinoid receptors,' which is a whole lot different than what the title of this Ars article says. You are right in so far as that the study itself had nothing to do with cannibinoids and everything to do with cannibinoid receptors. However, the title of this article implies that cannibinoids had something to do with this study, which from what little I could glean from the article and the introduction. A better title might have been, "Part of placebo effect ascribed to cannabinoid receptors," since it is the receptor that is the target of the study, and not cannabinoids. There is a big difference.

I did a little digging around. Feel free to correct me if the need arises, but the 'cannibinoids' which the body manufactures seems to be referred to as endocannabinoids rather than cannibinoids. So, maybe the problem here is with the author's/editor's choice for a title.

Anandamide is often referred to as an endogenous cannabinoid, certainly in my time working in the field we used that term rather than endocannabinoid, and anyway, the CB1 receptor is one of the two cannabinoid receptors and the pathways are cannabinoid pathways, so I think you're being a little overly prescriptive.

Goofball_Jones wrote:

Donnicton wrote:

So.... Essentially since placebo is meant to trick a test subject into thinking something is happening when it's not, they've effectively made a drug to partially block the imagination?

(Couldn't they have just sat their test subjects in front of a television and accomplished the same thing?)

Edit: Now that I think about it, how could this potentially be applied to situations of "opposite case scenarios", i.e. Hypochondriacs?

Well, it's been shown in several studies that the "placebo effect" is an actual chemical reaction, though still not fully understood. They gave patients a placebo morphine...just telling them they were getting morphine and the ones that responded to it were then secretly given a drug that blocks morphine, in other words, they weren't told at all they were getting the morphine blocker, and they started receiving pain again. The fake morphine was being blocked as if it were real.

I'll try to find the study and link it here. It's pretty fascinating.

"Chemical reaction" is not really the right term, biochemical pathway is more accurate.

As for the studies you're looking for, these are the ones referred to in the paper:

Why does this study remind me of those little rubber bracelets with magnets on both ends that give you more energy, improve your concentration and balance, increase your bloodflow, lower inherent probability of contracting cancer or ebola?

Why does this study remind me of those little rubber bracelets with magnets on both ends that give you more energy, improve your concentration and balance, increase your bloodflow, lower inherent probability of contracting cancer or ebola?

Also, I have to say.. Cannabinoids sound scary.

Why are they scary? They're no different to serotonin pathways, or dopamine pathways, or glutamate pathways, etc.

... These researchers are trying to figure out exactly how it works because this effect can be exploited to reduce pain without any harmful side effects...

Sugar is bad for you!

It will be interesting to see the spin both ways:

Cannabinoids keep your body from safely healing by not allowing the placebo trick to work?orCannabinoids help your body by keeping it alert to what's actually going on?

No, again, that's backwards. Rimbonant is a CB1 antagonist - that is, it blocks CB1 receptors from being activated, either by anandamide (which is produced by your body) or exogenous cannabiniods (like the bowl you just smoked). So cannabinoids are involved in causing the analgesic effect.

I'm not familiar with rimbonant. Is it correct to assume that if one smokes a joint and takes rimbonant the effect of the weed would diminish?

If you took rimbonant and then smoked weed, the rimbonant would prevent the weed from getting you high. Of course, you can't actually take it as it's not on the market - Sanofi tried it as an anti-obesity drug but unsurprisingly it caused people to be depressed and kill themselves.

Hmm, Pipeline. Maybe i should expand my reading beyond his colorful and deadpan descriptions of chemicals you do not want to tangle with (my main love being the concoction that can eat its way thru solid rock!).

Hmm, Pipeline. Maybe i should expand my reading beyond his colorful and deadpan descriptions of chemicals you do not want to tangle with (my main love being the concoction that can eat its way thru solid rock!).

Hmm, Pipeline. Maybe i should expand my reading beyond his colorful and deadpan descriptions of chemicals you do not want to tangle with (my main love being the concoction that can eat its way thru solid rock!).

Quote, "...to explain that in plain English, you give the subject a painful stimulus then give them an opioid to treat it..." It is a fact that pain can be helpful too. It helps diagnose a problem. If there is no pain, you have no idea that you have a medical problem that needs treatment.

It's my sense that this research insinuates something entirely different than the role of cannabinoids in the placebo response.

It seems to me that the authors have instead demonstrated two entirely different things:

1) That NSAIDS, in line with recent research that they mention in their introduction, probably work by activating CB1 receptors.

2) That the preconditioned(emphasis) placebo response, insomuch as it relates to pain, is probably mediated by the endogenous release of neurotransmitters that activate the same receptors as the preconditioning drug.

To me, this is an entirely different conclusion, because it doesn't imply that cannabinoids have a role in the preconditioned placebo effect generally, but only in the specific case where preconditioning activates cannabinoid receptors.

This is supported by the fact that cannabinoid blocking had no impact on the opioid preconditioned placebo response, but opioid blocking is well known to block it.

Additionally, it seems to me that the value of this research also has little to do with the placebo effect, but rather with the response to preconditioning, which, in my opinion, is somewhat misleadingly thought of as a placebo.

Where this research may be very useful is in the consideration of how the placebo response in a setting outside of preconditioning may work.

Wording my interpretation somewhat more colloquially, it seems this research implies that our body is unconsciously capable of recognizing and mimicking the pharmacologic behavior of a drug. So, can we also consciously control our ability to release endogenous "medicines" of our choosing?

I don't know, but lots of research certainly has shown meditation to be a decent pain-reliever...

Hmm, Pipeline. Maybe i should expand my reading beyond his colorful and deadpan descriptions of chemicals you do not want to tangle with (my main love being the concoction that can eat its way thru solid rock!).

I laughed. I cried. I got to the last comment (#56) and did a slow clap of conceding the internets have been won.

More constructively, this isn't the sort of post on Ars I usually check out, but I'm glad I did, because the comments (and the pipeline blog linked to by the comments) have taught me a few good things today

It's my sense that this research insinuates something entirely different than the role of cannabinoids in the placebo response.

It seems to me that the authors have instead demonstrated two entirely different things:

1) That NSAIDS, in line with recent research that they mention in their introduction, probably work by activating CB1 receptors.

I was about to flame you for this, since it's VERY well established that NSAIDS work by inhibiting cyclooxygenase (http://www.nobelprize.org/nobel_prizes/ ... ates/1982/) but a quick pubmed check shows me that there is now a body of work that implicates CB1 activity for some NSAIDS, and this might contribute to their antinociceptive effects. However, NSAIDS do more than just block pain, they're also anti-inflammatory, and that effect is definitely via the inhibition of COX-1 and COX-2 and the resulting reduction in prostanoid production.

Flame me? The well-established COX inhibition of NSAIDS isn't really relevant here. A pubmed search may not have been necessary - the authors note the novel NSAID/CB1 body of research in their introduction:

"There is accumulating evidence that the effects of NSAIDs go well beyond the inhibition of cyclooxygenase and prostaglandin synthesis. In fact, NSAIDs have been found to interact with endocannabinoids..."

Even if it isn't as well established as COX inhibition, the mere potential for cannabinoid involvement in the mechanism of NSAID analgesia is a significant detractor from their conclusion. This is particularly true considering the well known inhibition of opioid preconditioned placebo analgesia by opioid blocking.

I would have liked to have seen CB1 inhibition impact the opioid preconditioned group (or any convincingly non-cannabinoid analgesic pre-conditioned group) in order to be convinced that cannabinoids have an independent effect on placebo analgesia.